Genetic Testing Becomes Vital in Sequencing Treatments for Patients With Thyroid Cancer

Marcia Brose, MD, PhD

The treatment landscape for thyroid cancers has been enriched by several FDA approvals of targeted therapies, underscoring the importance for conducting genetic testing on patients with thyroid cancer before making treatment decisions.

Larotrectinib (Vitrakvi) was approved by the FDA in 2019 for the treatment of patients with solid tumors harboring an NTRK gene fusion. Entrectinib (Rozlytrek) was approved in 2019 for the treatment of patients with solid tumors harboring an NTRK gene fusion as well. While these fusions may be rarer in select cancer types, it is still important to test for this gene because both larotrectinib and entrectinib have been associated with more tolerable toxicity profiles compared with other available treatments.

Outside of TRK fusions, a RET inhibitor was also approved by the FDA, selpercatinib (LOXO-292), as treatment of patients with lung cancer or thyroid cancer harboring RET alterations. In thyroid cancer, this indication is specified for patients with advanced or metastatic RET-mutant medullary thyroid cancer or those with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory.

The approval of these targeted therapies in thyroid cancer suggests that physicians should be testing their patients for potential gene fusions or alterations. More therapies are under review in clinical trials or by the FDA for different therapies in thyroid cancer that will also rely on results from genetic testing. The highly selective RET inhibitor pralsetinib (BLU-667), for example, is under investigation now and has shown encouraging findings in thyroid cancer.

In an interview with Targeted Oncology, Marcia Brose, MD, PhD, director of the Center for Rare Cancers and Personalized Therapy, director of the Thyroid Cancer Therapeutics Program, associate professor of Otorhinolaryngology: Head and Neck Surgery at the Hospital of the University of Pennsylvania, and associate professor of Medicine at Penn Medicine, discussed the role of genetic testing in patients with thyroid cancer and the current treatment landscape.

TARGETED ONCOLOGY: How frequently are NTRK gene fusions observed in thyroid cancer?

Brose: NTRK gene fusions can be anywhere from extremely rare, less than 1% in a certain cancer to quite common in over 25% [with another cancer]. One of the things we know is that it is a little more common in both papillary thyroid cancer and metastatic colorectal cancer, which has microsatellite instability-high (MSI-H). MSI-H is 1 of the markers we check regularly in colon cancers, but it is probably in many other cancers as well.

TARGETED ONCOLOGY: What does prognosis look like for these patients?

Brose: For patients who have metastatic colorectal cancer that has not been responsive to other agents or metastatic thyroid cancer and no matter what therapies are available, they inevitably work for only so long. At that time, the prognosis starts to become quite grim. For patients with metastatic disease who are not cured, the prognosis depends on whether they have just been diagnosed or had not been diagnosed, had a lot of disease or not a lot of disease. The bottom line is they will not be cured. Even with all the therapies that we have, including the ones that work, they do not work forever. For that reason, we need to keep finding additional therapies that will help.

TARGETED ONCOLOGY: How often should physicians be conducting genomic testing for their patients with thyroid cancer? Do you think we are doing this enough right now?

Brose: We have enough targeted therapies now for thyroid cancer that we should know what the genetic and genomic landscape is for our patients before we even start any systemic therapy. The reason for that is 2-fold. First of all, this has to do with treatment planning. You may want to sequence the different therapies that are available in a certain way based on what you know is going to be available for the patient. The second very important thing is all the approved agents are not the same when it comes to tolerability. If a patient has access to a more tolerable agent because of a genetic marker in the tumor, you would want to know that because perhaps you would start with that and not have to deal with maybe quite as high a side effect profile.

TARGETED ONCOLOGY: Do you want to discuss these targeted therapies?

Brose: Currently for TRK fusion cancers, there are 2 FDA-approved agents. The first is larotrectinib, and the second is called entrectinib. Both of these agents target the TRK fusion, and the TRK fusion is the TRK gene that is stuck together with another gene. When things are stuck together, that activates that pathway, so much so that we think it caused that cancer to begin with. What we do is we test for those, and if we can actually target that abnormal pathway with an agent, we have a chance of directly getting at the cause of cancer. Both larotrectinib and entrectinib do a good job at inhibiting the TRK fusion gene. As a result, they do a good job at stopping these cancers from growing. In many cases, it causes quite a significant amount of shrinkage, so much so that sometimes the shrinkage is so great you cannot even find the disease anymore. I would never say the word cure because we don’t have any data to say people are cured, but getting the disease burden down to be so small that we cannot find it on a CAT scan, that is a new level of response we have not been able to achieve with other agents.

TARGETED ONCOLOGY: How do you sequence agents in patients with thyroid cancer?

Brose: We look at treating these patients. We say if you find a patient who has a TRK fusion, when we start them on therapy, they have a choice of starting with the TRK gene with either larotrectinib or entrectinib or starting on the FDA-approved lenvatinib (Lenvima) or sorafenib (Nexavar). Both lenvatinib and sorafenib, while they have been very useful and active agents, they do have a side effect profile. Larotrectinib and entrectinib have better side effect profiles, so patients do not experience as many issues with high blood pressure, skin issues, or even fatigue. For that reason, if I have that option and they do have a TRK gene fusion, I am likely to choose that in the first place. I would use [larotrectinib or entrectinib] as first-line therapy.

I will point out that TRK fusions are still the minority of these patients. It is important to know if they have it or not, so we probably will not be using this in a lot of people. However, it is 1 of those instances where we have a really good therapy that you don’t want to miss in 1 of your patients.

TARGETED ONCOLOGY: Besides these fusions, are there other fusions or mutations physicians should be testing for now?

Brose: Interestingly, a RET inhibitor, selpercatinib, was recently approved by the FDA. In metastatic differentiated thyroid cancer, there is a small population of patients who have RET fusions. In addition, patients with medullary thyroid cancer have RET-point mutations. In my opinion, given the ability, I would prefer to check both genetic and genomic.

TARGETED ONCOLOGY: Are there any other new treatments coming down the pipeline in thyroid cancer?

Brose: The most exciting thing happening right now are the RET inhibitors. Selpercatinib was approved recently by the FDA, and pralsetinib is another that is probably going to become approved in the coming year. This has been a game changer for patients with metastatic medullary thyroid cancer, as well as the subtype of differentiated thyroid cancer. Those are exciting the most.

We are still finding out whether immunotherapy has a role. At this point, the data has not lived up to what I had hoped, so I do not feel that right now we have a big immunotherapy combination I’m excited about. However, I’m still waiting on some more data in the coming year, and hopefully there will be some good combinations of immunotherapy with the kinase inhibitors that are already approved.

TARGETED ONCOLOGY: What is your key takeaway on the treatment landscape right now?

Brose: I personally feel that all patients with solid tumors who have metastatic disease and are not curable, they should all have genetic testing done to find if they have any point mutations or gene fusions. At a minimum, many of the mutations we find by doing genetic testing has a prognostic indication, meaning knowing a genetic mutation may change what we expect as far as how well a patient will do. In many cases, more than just being prognostic, it can also predict responses to some of these new agents that are a new level of agents that can create a very good response with really tolerable, if any, side effects. I think it is exciting because we have not had these agents up until now. As a physician, this is something I think we all need to know about.